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CEPHALOSPORINS

CEPHALOSPORINS. Dr. Naila Abrar. LEARNING OBJECTIVES . After this session you should be able to: know the source and chemistry of cephalosporins; classify cephalosporins and comprehend the basis of classification; describe salient pharmacokinetic properties of various cephalosporins;

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CEPHALOSPORINS

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  1. CEPHALOSPORINS Dr. Naila Abrar

  2. LEARNING OBJECTIVES After this session you should be able to: • know the source and chemistry of cephalosporins; • classify cephalosporins and comprehend the basis of classification; • describe salient pharmacokinetic properties of various cephalosporins; • describe the MOA • explain the spectrum of activity & clinical uses of different classes of cephalosporins; and • describe the adverse effects of cephalosporins.

  3. HISTORY • Brotzu(1945) isolated a mold Acremoniumchrysogenumin sewer water off coast of Sardinina • First introduced into clinical use in 1964 (cephalothin)

  4. CHEMISTRY • Derivatives of 7-aminocephalosporanic acid • Water soluble; stable to pH & temperature changes • More stable than penicillins • Cephamycins: methoxy at position7 • Oxycepems: sulfur replaced by oxygen at position 1 • Carbacepteus: sulfur replaced by carbon atom at 1

  5. CLASSIFICATION • Based on spectrum of activity • Divided into four “Generations” for convenience but many drugs in same “Generation” are not chemically related & having different spectrum of activity

  6. Major criteria: spectrum of activity • As gm +ve decreases gm –ve increases Minor criteria: b-lactamase resistance • 1st gen most sensitive, 2nd gen have better tolerability, 3rd gen tolerate even better but susceptible to hydrolysis by inducible chromosomally encoded type 1 b-lactamases & induction during treatment of gm –ve infections, 4th gen have increased stability to hydrolysis by plasmid & chromosomally mediated b-lactamases Third criteria:Ability to cross BBB • 1st do not, 2nd only cefuroxime does, 3rd ceftriaxone & ceftazidime, 4th all Fourth criteria: route of administration • All classes sub classified into oral and pareneteral

  7. Classification FIRST GENERATION • (G + ve sensitive) • Klebsiella, proteus (non indole positive only), E. coli • Parenteral: • Cephalothin, cefazolin • Oral: • Cefadroxil, cephalexin, cephradine

  8. SECOND GENERATION • Gram positive organisms (including those resistant to 1st generation) • Klebsiella, proteus (including indole positive) H. Influenzae • Parenteral: Cefuroxime, cefamandole, cefoxitin (good activity against anaerobes) • Oral: Cefaclor, cefuroxime axetil, cefprozil, loracarbef

  9. THIRD GENERATION • g-ve organisms including citrobacter, acinetobacter, serratia, providencia, enterobacter, salmonella} • pseudomonas sensitive only to ceftazidime & cefoperazone • Parenteral: Ceftriaxone, cefotaxime, ceftazidime, ceftizoxime, cefoperazone • Oral: Cefixime • Bacteroidesfragilisis sensitive to: Cefoxitin, Cefametazol, cefotetane

  10. Fourth Generation • Cefepime • Gram +ve &gram -ve: Fourth-generation cephalosporins are “zwitterions”that can penetrate the outer membrane of gram-negative bacteria • Spectrum same but differ in resistance to b-lactamases • Cefclidine, Cefepime(Maxipime), Cefluprenam, Cefoselis, Cefozopran, Cefpirome(Cefrom), Cefquinome

  11. Cont: 4th generation • Pseudomonas aeruginosa • Klebsiellapneumoniaeor enterobacterspp. • Proteus mirabilis, escherichiacoli • Streptococcus pyogenes • Bacteroidesfragilis • Staphylococusaureus(methicillin-susceptible strains only)

  12. FIFTH GENERATION (terminology not accepted widely) • Ceftobiprole • Ceftaroline • Ceftobiprolehas powerful antipseudomonal characteristics and appears to be less susceptible to development of resistance. • Ceftarolinehas also been described as "fifth-generation" cephalosporin, but does not have the anti-pseudomonaleffect.

  13. ORGANISMS RESISTANT TO CEPHALOSPORINS • Listeria monocytogenes • Atypicals (Mycoplasma, Chlamydia) • MRSA ?( CEFEPIME) • Enterococci

  14. MECHANISM OF ACTION • Cell wall synthesis inhibitors • Bactericidal • Similar to penicillins

  15. MECHANISM OF RESISTANCE • Changes in drug target proteins PBP • EFFLUX PUMPS (Pseudomonas aeruginosa) • Decreased permeability of cell wall ? • Hydrolysis by b-lactamases (plasmid mediated) CROSS RESISTANCE • Resistance to other  Lactam antibiotic

  16. PHARMACOKINETICS ROUTE:Oral, IV, IM • Cephalothin, cephapirin pain by IM DOSE:single shot therapy • Cefonicid, ceftriaxone, ceforanide METABOLISM • Cephalothin, cephapirin, cefotaxime are deacetylated • Cefuroximeaxetil is hydrolyzed by liver into cefuroxime

  17. DISTRIBITION • Synovial, pericardial fluids • Cross BBB 3rd & 4th generations EXCRETION • Kidney- tubular secretion • Bile (ceftriaxone, cefoperazone)

  18. THERAPEUTIC USES of 1st Generation • Surgical prophylaxis (cefazolin) • UTI • Cellulitis • Soft tissue abcess • Alternative to antistaphylococcal penicillins in case of allergy

  19. THERAPEUTIC USES of 2nd Generation • b-lactamase producing H influenza, moraxellacatarrhalis • Sinusitis • Otitis media • LRTI • Peritonitis • Diverticulitis • CAP

  20. Clinical Uses of 3rd Generation • Lower respiratory tract infections • Acute bacterial otitis media • Skin and skin structure infections • Urinary tract infections (complicated and uncomplicated) • Bacterial septicemia • Bone and joint infections intra-abdominal infections • Meningitis (H. influenzae, N. meningitidis, S. pneumoniae)

  21. THERAPEUTIC USES of CEFEPIME (4th generation) • Empiric therapy for febrile neutropenicpatients.   • Pneumonia (moderate to severe) caused by Streptococcus pneumoniae, including bacteremia, Pseudomonas aeruginosa , Klebsiellapneumoniae, or Enterobacterspecies. • Uncomplicated and complicated UTIs (including pyelonephritis) caused by Escherichia coli or Klebsiellapneumoniae, Escherichia coli , Klebsiellapneumoniae, or Proteus mirabilis ,

  22. Uncomplicated skin and skin structure infections caused by Staphylococcus aureus(methicillin-susceptible strains only) or Streptococcus pyogenes • Complicated intra-abdominal infections ( in combination with metronidazole) caused by Escherichia coli, streptococci, Pseudomonas aeruginosa, Klebsiellapneumoniae, Enterobacterspecies, or Bacteroidesfragilis

  23. ADVERSE EFFECTS • Hypersensitivity • Local irritation • Severe pain after IM inj • Thrombophlebitis after IV inj • Superinfection • Pseudomembranous colitis • Dose dependent nephrotoxicity • Interstitial nephritis • Disulfiram like effects • Bleeding disorders • Diarrhea

  24. Thank You!

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